An antibacterially active quinolone or naphthyridonecarboxylic acid derivative of the formula ##STR1## in which R1 stands for various organic radical, R2 stands for hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, R3 stands for hydrogen or amino, R4 stands for a radical...http://www.google.com/patents/US5284842?utm_source=gb-gplus-sharePatent US5284842 - Active against gramnegative bacteria

An antibacterially active quinolone or naphthyridonecarboxylic acid derivative of the formula ##STR1## in which R1 stands for various organic radical,

R2 stands for hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,

R3 stands for hydrogen or amino,

R4 stands for a radical of the formula ##STR2## A stands for N or C--R5, wherein

R5 stands for hydrogen, halogen methyl, cyano or nitro or else together with R1 can form a bridge of the structure ##STR3## or a pharmaceutically utilizable hydrate, acid addition salt, alkali metal salt, alkaline earth metal salt, silver salt or guanidinium salt of the carboxylic acid when R2 is hydrogen.

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Claims(4)

What is claimed is:

1. A quinolonecarboxylic acid of the formula ##STR94## in which p stands for 1 or 2,

2. A compound according to claim 1, in which said compound is 1-cyclopropyl-7-(4-ethylaminomethyl-4-hydroxy-1-piperidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula ##STR95##

3. An anti-bacterial composition comprising an antibacterially effective amount of a compound according to claim 1 and a pharmaceutically acceptable diluent.

4. A method of combating bacterial in a patient which comprises administering to such patient an antibacterially effective amount of a compound according to claim 1.

Description

This application is a division of application Ser. No. 699,880, filed May 14, 1991, now U.S. Pat. No. 5,173,484, which is a continuation-in-part of application Ser. No. 298,459, filed Jan. 18, 1989, now abandoned.

The invention relates to quinolone- and naphthyridonecarboxylic acid derivatives which are substituted in the 7-position by a cyclic amine radical which carries a quaternary carbon atom, processes for their preparation, and antibacterial agents and feed additives containing them.

It has been found that quinolone- and naphthyridonecarboxylic acid derivatives of the formula (I) ##STR4## in which R1 stands for methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl,

R2 stands for hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,

R3 stands for hydrogen or amino,

R4 stands for a radical of the formula ##STR5## excluding 3-amino-3-methyl-1-pyrrolidinyl, wherein

p stands for 0, 1 or 2,

m stands for 1 or 2, where p+m together can be 1, 2 or 3,

n stands for 1 or 2,

Y stands for ##STR6## OR, SR, halogen or hydrogen, X1 stands for ##STR7## OR, SR, halogen, CN, CONH2, COOH or C1 -C4 -alkyl, X2 and X3 can be identical or different and stand for oxygen, sulphur, NH or N--CH3,

R stands for hydrogen, C1 -C3 -alkyl or C1 -C3 -acyl,

R' stands for hydrogen, C1 -C3 -alkyl, allyl or propargyl and

R" stands for hydrogen, C1 -C3 -alkyl or C3 -C6 -cycloalkyl,

where

R'+R" together can also denote the groups --CH2 CH2 --O--CH2 CH2 -- or --(CH2)k --, in which

k can stand for 3, 4 or 5,

R"' stands for hydrogen or C1 -C3 -alkyl,

A stands for N or C--R5,

wherein

R5 stands for hydrogen, halogen such as fluorine or chlorine, methyl, cyano or nitro or else together with R1 can form a bridge of the structure ##STR8## and their pharmaceutically utilizable hydrates and acid addition salts and also the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts of the underlying carboxylic acids, have a high antibacterial action, in particular in the gram-positive range.

They are therefore suitable as active compounds for human and veterinary medicine, the treatment of fish for the therapy or prophylaxis of bacterial infections being included in the term veterinary medicine.

R2 stands for hydrogen, alkyl having 1 to 3 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,

R3 stands for hydrogen or amino,

R4 stands for a radical of the formula ##STR9## excluding 3-amino-3-methyl-1-pyrrolidinyl, wherein

p stands for 0, 1 or 2,

m stands for 1 or 2, where p+m together can be 1, 2 or 3,

n stands for 1 or 2,

Y stands for ##STR10## OR, or hydrogen, X1 stands for ##STR11## OR, fluorine, chlorine or C1 -C2 -alkyl, X2 and X3 can be identical or different and stand for oxygen, sulphur or N--CH3,

R stands for hydrogen, C1 -C2 -alkyl or acetyl,

R' stands for hydrogen or C1 -C2 -alkyl, and

R" stands for hydrogen or C1 -C2 -alkyl,

where

R'+R" together also denote the groups --CH2 CH2 --O--CH2 CH2 -- or --(CH2)k, in which k can stand for 3, 4 or 5,

R"' stands for hydrogen or C1 -C2 -alkyl and

A stands for N or C--R5,

wherein

R5 stands for hydrogen, halogen such as fluorine or chlorine or methyl or else together with R1 can form a bridge of the structure ##STR12## and their pharmaceutically utilizable hydrates and acid addition salts and also the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

Particularly preferred compounds of the formula (I) are those in which

R4 stands for a radical of the formula ##STR13## excluding 3-amino-3-methyl-1-pyrrolidinyl, wherein

p stands for 0, 1 or 2,

m stands for 1 or 2, where p+m together can be 1, 2 or 3,

n stands for 1,

Y stands for ##STR14## OR or hydrogen, X1 stands for ##STR15## OR, chlorine or methyl, X2 and X3 can be identical or different and stand for oxygen or N--CH3,

R stands for hydrogen or methyl,

R' stands for hydrogen or methyl,

R" stands for hydrogen or methyl,

R"' stands for hydrogen or methyl and

A stands for N or C--R5,

wherein

R5 stands for hydrogen, halogen, such as fluorine or chlorine or else together with R1 can form a bridge of the structure ##STR16## and their pharmaceutically utilizable hydrates and acid addition salts and also the alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.

Furthermore, it has been found that the compounds of the formula (I) are obtained when compounds of the formula (II) ##STR17## in which Z stands for fluorine or chlorine and

R1, R2, R3 and A have the abovementioned meaning,

are reacted with compounds of the formula (III)

R4 --H (III)

in which

R4 has the abovementioned meaning,

if appropriate in the presence of acid entrainers.

Compounds of the structure (Ia) ##STR18## in which R1, R2, R3, R"', A, X2, X3, m and p have the abovementioned meaning,

can also be prepared by reaction of a compound of the formula (IV) ##STR19## in which R1, R2, R3, R"', A, m and p have the above-mentioned meaning,

with a compound of the formula (V)

H--X2 --CH2 --CH2 --X3 --H (V)

in which

X2 and X3 have the abovementioned meaning.

If, for example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 3-ethylaminomethyl-3-hydroxy-pyrrolidine are used as starting substances, then the course of the reaction can be represented by the following equation: ##STR20##

The compounds of the formula (II) used as starting substances are known or can be prepared by known methods. Examples which may be mentioned are:

The compounds of the formula (III) used as starting compounds are in some cases new and therefore an embodiment of the present invention.

Their preparation can be carried out by various processes:

1. Ring-opening to form the hydroxyamines (3) is carried out by reaction of the spiro-oxiranes protected on the nitrogen (1) [J. Med. Chem. 30, 222 (1987); U.S. Pat. No. 4,508,724; EP 189,370] with amines (2). Elimination of the protective group yields starting compounds of the formula (IIIa): ##STR21##

2. The cyclization of the succinic acid ester (4) [Tetrahedron Letters 46, 4561 (1973)] with benzylamine yields the alkyl 1-benzyl-3-hydroxy-5-oxo-pyrrolidine-3-carboxylate (5) which, after reaction with an amine (2), reacts to give the amide (6). Subsequent reduction with LiAlH4 and hydrogenolytic elimination of the benzyl group yields starting compounds of the formula (IIIb): ##STR22##

3. Reaction of the (1-benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl)-acetic acid (7) [Gazz. Chim. Ital. 24, 226 (1984)] to give the amide (8) and subsequent reduction using LiAlH4 and elimination of the benzyl group yields starting compounds of the formula (IIIc): ##STR23##

5. Starting from cyclic oxoamines (9) which are blocked by a protective group on the nitrogen, starting compounds of the formulae (IIId), (IIIe) and (IIIf) can be synthesized [Acta Chem. Scand. B 34, 319 (1980)]. ##STR24##

6. The hydroxy group of the hydroxyamines (IIIa)-(IIIf) can be alkylated or halogenated.

By reaction of the spiro-oxiranes protected on the nitrogen (1) with trimethylsilyl cyanide [J. Amer. Chem. Soc. 104, 5849 (1982)], the isonitriles (14) can be prepared which can be reacted by hydrolyzing and eliminating the protective group to give the starting compounds of the formula (IIIg): ##STR25##

Examples of starting compounds of the formula (III) which may be mentioned are the following compounds, where chiral compounds can be employed both as racemates as well as pure enantiomeric substances:

3-aminomethyl-3-hydroxypyrrolidine,

3-acetylaminomethyl-3-hydroxypyrrolidine,

3-tert.-butoxycarbonylaminomethyl-3-hydroxypyrrolidine,

3-hydroxy-3-methylaminomethylpyrrolidine,

3-ethylaminomethyl-3-hydroxypyrrolidine,

3-hydroxy-3-propylaminomethylpyrrolidine,

3-ethylaminomethyl-3-methoxypyrrolidine,

3-aminomethyl-3-fluoropyrrolidine,

3-aminomethyl-3-chloropyrrolidine,

3-fluoro-3-methylaminomethylpyrrolidine,

3-chloro-3-methylaminomethylpyrrolidine,

3-ethylaminomethyl-3-fluoropyrrolidine,

3-chloro-3-ethylaminomethylpyrrolidine,

3-hydroxy-3-methylpyrrolidine,

3-hydroxy-3-methoxymethylpyrrolidine,

3-methoxy-3-methylaminomethylpyrrolidine,

3-dimethylaminomethyl-3-fluoropyrrolidine,

3-chloro-3-dimethylaminomethylpyrrolidine,

3-fluoromethyl-3-aminopyrrolidine,

3-ethoxy-3-ethylaminomethylpyrrolidine,

3-chloro-3-ethylaminomethylpyrrolidine,

3-ethylaminomethyl-3-fluoropyrrolidine,

3-ethylaminomethyl-3-methylpyrrolidine,

3-ethylaminomethyl-3-mercaptopyrrolidine,

3-ethylaminomethyl-3-methylthiopyrrolidine,

3-acetoxy-3-ethylaminomethylpyrrolidine,

3-dimethylaminomethyl-3-hydroxypyrrolidine,

3-hydroxy-3-pyrrolidinomethylpyrrolidine,

3-hydroxy-3-morpholinomethylpyrrolidine,

3-amino-3-ethylaminomethylpyrrolidine,

3-acetylamino-3-ethylaminomethylpyrrolidine,

3-ethylaminomethyl-3-methylaminopyrrolidine,

3-dimethylamino-3-ethylaminomethylpyrrolidine,

3-amino-3-hydroxymethylpyrrolidine,

3-acetylamino-3-hydroxymethylpyrrolidine,

3-amino-3-methoxymethylpyrrolidine,

3-tert.butoxycarbonylamino-3-methoxymethylpyrrolidine,

3-amino-3-methylthiomethylpyrrolidine,

3-amino-3-mercaptomethylpyrrolidine,

3-cyclopropylaminomethyl-3-hydroxypyrrolidine,

3-isopropylaminomethyl-3-hydroxypyrrolidine,

1,4-dioxa-7-azaspiro[4.4]nonane,

1-oxa-4,7-diazaspiro[4.4]nonane,

4-methyl-1-oxa-4,7-diazaspiro[4.4]nonane,

1-thia-4,7-diazaspiro[4.4]nonane,

1,4,7-triazaspiro[4.4]nonane,

1,4-dimethyl-1,4,7-triazaspiro[4.4]nonane.

The reaction of (II) with (III) is preferably performed in a diluent such as dimethyl sulphoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, sulpholane, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether, acetonitrile or pyridine. Mixtures of these diluents can likewise be used.

All customary inorganic and organic acid-binding agents can be used as acid binders. These preferably include the alkali metal hydroxides, alkali metal carbonates, sodium hydride, organic amines and amidines. Those which may be mentioned individually as being particularly suitable are: triethylamine, 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or excess amine (III).

The reaction temperatures can be varied within a relatively wide range. In general, the reaction is carried out between about 20° and 200° C., preferably between 80° and 180° C.

The reaction can be carried out at atmospheric pressure, but also at elevated pressure. In general, the reaction is carried out at pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention by method A, 1 to 15 moles, preferably 1 to 6 moles, of the amine (III) are employed per mole of carboxylic acid (II).

In addition to the compounds shown in the examples, the following may be mentioned individually as new active compounds:

The compounds according to the invention show, combined with low toxicity, a broad antibacterial spectrum against gram-positive and gram-negative bacteria, in particular against Enterobacteriaceae; above all also against those which are resistant to various antibiotics, such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines.

These useful properties facilitate their use as chemotherapeutically active compounds in medicine and also as substances for the preservation of inorganic and organic materials, in particular of organic materials of all types, for example polymers, lubricants, dyes, fibers, leather, paper and wood, and of foodstuffs and water.

The compounds according to the invention are active against a very wide spectrum of microorganisms. Gram-negative and gram-positive bacteria and bacteria-like microorganisms can be controlled with their aid, and the diseases produced by these pathogens can also be prevented, improved and/or cured.

The compounds according to the invention are particularly active against bacteria and bacteria-like microorganisms. They are therefore particularly well suited in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections which are produced by these pathogens.

Bacterial diseases in the rearing and keeping of productive and ornamental fish can likewise be treated, where the antibacterial spectrum is widened beyond the previously mentioned pathogens to further pathogens such as, for example, Pasteurella, Rucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia, Yersinia and Aeromonas, Edwardsiella and Vibria.

The present invention includes pharmaceutical preparations which contain one or more according to the invention or which consist of one or more active compounds according to the invention in addition to non-toxic, inert pharmaceutically suitable excipients and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual portions, for example tablets, dragees, capsules, pills, suppositories and ampoules, whose active compound content corresponds to a fraction or a multiple of an individual dose. The dosage units may contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose.

Non-toxic, inert pharmaceutically suitable excipients are taken to mean solid, semi-solid or liquid diluents, fillers or formulation auxiliaries of any type.

The tablets, dragees, capsules, pills and granules may be provided with the customary coatings and shells containing, if appropriate, opacifying agents and can be so composed that they release the active compound(s), if appropriate with a delay, only or preferably in a certain part of the intestinal tract, in which case, for example, polymeric substances and waxes can be used as embedding materials.

If appropriate, the active compound(s) may also be present in micro-encapsulated form with one or more of the abovementioned excipients.

In addition to the active compound(s), suppositories may contain the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C14 -alcohol with C16 -fatty acid) or mixtures of these substances.

Powders and sprays may contain the customary excipients in addition to the active compound(s), for example lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain the customary propellants, for example chlorofluorohydrocarbons.

The said formulation forms may also contain colorants, preservatives and also odour-improving and flavour-improving additives, for example peppermint oil and eucalyptus oil and sweeteners, for example saccharin.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight, of the total mixture.

The abovementioned pharmaceutical preparations may also contain further pharmaceutical active compounds in addition to the compounds according to the invention.

The preparation of the abovementioned pharmaceutical preparations takes place in a customary manner by known methods, for example by mixing the active compound(s) with the excipient(s).

The preparations mentioned may be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powders, ointments, drops) and for the therapy of infections in hollow spaces and body cavities. Suitable preparations are injection solutions, solutions and suspensions for oral therapy, gels, pour-on formulations, emulsions, ointments or drops. For local therapy, ophthalmological and dermatological formulations, silver salts and other salts, ear drops, eye ointments, powders or solutions may be used. In animals, the administration may also take place in suitable formulations via the feed or drinking water. Furthermore, gels, powders, tablets, delayed-release tablets, premixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays and inhalants may be used in humans and animals. Furthermore, the compounds according to the invention may be incorporated into other excipients such as, for example, plastics, (plastic chains for local therapy), collagen or bone cement.

In general, it has proved advantageous both in human and veterinary medicine to administer the active compound(s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to attain the desired results. An individual dose preferably contains the active compound(s) according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight. However, it may be necessary to depart from the dosages mentioned, depending on the type and the body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the administration of the medicament and also the time period or interval within which the administration takes place.

Thus in some cases it may be sufficient to manage with less than the abovementioned amount of active compound, whereas in other cases the abovementioned amount of active compound must be exceeded. The optimum dosage required in each case and the type of administration of the active compounds can easily be established by anyone skilled in the art on the basis of his expert knowledge.

The new compounds may be given in the customary concentrations and preparations together with the feed or feed preparations or with the drinking water. Infection by gram-negative or gram-positive bacteria can thus be prevented, improved and/or cured and promotion of growth and an improvement in the utilization of the feed can thus be achieved.

The minimum inhibitory concentrations (MIC) were determined by the serial dilution method on iso-sensitest agar (Oxoid). A series of agar plates which contained concentrations of the active compound decreasing in double dilutions in each case were prepared for each test substance. The agar plates were inoculated using a multi-point inoculator (Denley). For the inoculation, overnight cultures of the pathogen were used which were previously diluted in such a way that each inoculation point contained about 104 colony-forming particles. The inoculated agar plates were incubated at 37° C. and the bacterial growth was read off after about 20 hours. The MIC value (μg/ml) indicates the lowest active compound concentration with which no bacterial growth could be detected using the naked eye.

In the table below, the MIC values of some of the compounds according to the invention are indicated in comparison to ciprofloxacin and norfloxacin.

23.5 g (107 mmol) of trimethylsulphoxonium iodide and 3.3 g of sodium hydride (80% strength in paraffin oil) are initially introduced and 80 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. The mixture is stirred for an hour at room temperature and 15.7 g (100 mmol) of ethyl 3-oxopyrrolidine-1-carboxylate [J. Med. Pharm. Chem. 5, 752 (1962)] in 20 ml of absolute dimethyl sulphoxide are then added dropwise in the course of 15 minutes. The mixture is stirred for one hour at room temperature, poured onto a mixture of ice and saturated sodium chloride solution and extracted using diethyl ether. The ether solutions are washed with sodium chloride solution, dried over Na2 SO4, concentrated and distilled.

Yield: 6 g

Boiling point: 80° C./0.15 mbar

b) Ethyl 3-ethylaminomethyl-3-hydroxypyrrolidine-1-carboxylate

8 g (46.7 mmol) of ethyl 5-aza-1-oxaspiro[2,4]heptane-5-carboxylate are added dropwise to 50 ml of ethylamine solution (50% in water) and the mixture is stirred overnight at room temperature. It is concentrated and the residue is distilled.

Yield: 8 g

Boiling point: 130° C./0.05 mbar

c) 3-Ethylaminomethyl-3-hydroxypyrrolidine

7.7 g (35.6 mmol) of ethyl 3-ethylaminomethyl-3-hydroxypyrrolidine-1-carboxylate are heated under reflux overnight with 22 g of Ba(OH)2. 8H2 O in 220 ml of water. The mixture is filtered off with suction from BaCO3 and concentrated. The residue is boiled five times using 100 ml of dioxane each time, and the dioxane solution is concentrated and distilled.

9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane (U.S. Pat. No. 4,508,724) are added dropwise to 50 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.

Yield: 4.4 g

Boiling point: 134° C./0.4 mbar

b) 3-Aminomethyl-3-hydroxypyrrolidine

3.9 g (18.9 mmol) of 3-aminomethyl-1-benzyl-3-hydroxypyrrolidine in 25 ml of methanol are hydrogenated using 1 g of palladium/active carbon (10%) at 90° C. and 95 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

10.2 g (53.9 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane are added dropwise to 60 ml of aqueous ethylamine solution (50%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.

Yield: 10.7 g

Boiling point: 120° C./0.18 mbar

b) 3-Ethylaminomethyl-3-hydroxypyrrolidine

10 g (42.7 mmol) of 1-benzyl-3-ethylaminomethyl-3-hydroxypyrrolidine in 60 ml of methanol are hydrogenated using 2 g of palladium/active carbon (10%) at 92° C. and 107 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

10.2 g (58.3 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane are added dropwise to 70 ml of aqueous methylamine solution (30%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.

Yield: 8.8 g

Boiling point: 145° C./0.35 mbar

The distillate is dissolved in dilute hydrochloric acid and the solution is concentrated. The crystalline residue is triturated with isopropanol, filtered off with suction and dried.

Yield: 7.3 g

Melting point: 202° C.

b) 3-Hydroxy-3-methylaminomethylpyrrolidine dihydrochloride

6.9 g (23.5 mmol) of 1-benzyl-3-hydroxy-3-methylaminomethylpyrrolidine dihydrochloride in 100 ml of methanol are hydrogenated on 2 g of palladium/active carbon (10%) at 80° C. and 100 bar. The catalyst is filtered off with suction, the solution is concentrated and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.

9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane are added dropwise to 9.7 g (0.17 mol) of cyclopropylamine in 40 ml of water and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.

Yield: 8 g

Boiling point: 130° C./0.08 mbar

The distillate is dissolved in dilute hydrochloric acid and the solution is concentrated. The residue which crystallizes is triturated with acetone, filtered off with suction and dried.

Yield: 8.3 g

Melting point: 182°-184° C.

b) 3-Cyclopropylaminomethyl-3-hydroxypyrrolidine dihydrochloride

7.9 g (24.7 mmol) of 1-benzyl-3-cyclopropylaminomethyl-3-hydroxypyrrolidine dihydrochloride in 100 ml of methanol are hydrogenated on 2 g of palladium/active carbon (10%) at 50° C. and 100 bar. The product is filtered off with suction and concentrated, and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.

23.5 g (107 mmol) of trimethylsulphoxonium iodide and 3.4 g (100 mmol) of NaH (80% in paraffin oil) are initially introduced and 80 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. The mixture is stirred for one hour at room temperature and 15.8 g (100 mmol) of methyl 3-piperidone-1-carboxylate [Acta Chem. Scand. B 30, (1976), page 884] are then added dropwise in the course of 15 minutes. The mixture is stirred for one hour at room temperature, poured onto a mixture of ice and saturated sodium chloride solution and extracted using diethyl ether. The ether solution is washed with sodium chloride solution, dried over Na2 SO4, concentrated and distilled.

Yield: 8 g

Boiling point: 68° C./0.15 mbar

b) Methyl 3-aminomethyl-3-hydroxypiperidine-1-carboxylate

9.1 g (53.2 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.

Yield: 5.6 g

Boiling point: 103° C./0.1 mbar

c) 3-Aminomethyl-3-hydroxypiperidine

5.1 g (27.1 mmol) of methyl 3-aminomethyl-3-hydroxypiperidine-1-carboxylate are heated overnight under reflux with 15.8 g of Ba(OH)2. 8H2 O in 150 ml of water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 70 ml of dioxane each time, and the dioxane solutions are concentrated and distilled.

9.3 g (54.3 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of methylamine solution (25% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.

Yield: 9.2 g

Boiling point: 83°-95° C./0.1 mbar

b) 3-Hydroxy-3-methylaminomethylpiperidine

8.7 g (43 mmol) of methyl 3-hydroxy-3-methylaminomethylpiperidine-1-carboxylate are heated overnight under reflux with 24 g of Ba(OH)2. 8H2 O in 240 ml of water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 100 ml of dioxane each time, and the dioxane solution is concentrated and distilled.

9.3 g (54.3 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of ethylamine solution (50% strength in water) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.

Yield: 11.2 g

Boiling point: 104°-108° C./0.2 mbar

b) 3-Ethylaminomethyl-3-hydroxypiperidine

10 g (46.2 mmol) of methyl 3-ethylaminomethyl-3-hydroxypiperidine-1-carboxylate are heated under reflux overnight with 28.5 g of Ba(OH)2. 8H2 O in 280 ml of water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 120 ml of dioxane each time, and the dioxane solution is concentrated and distilled.

13.4 g (72.3 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate (European Patent Application 189,370) are added dropwise to 60 ml of ammonia solution (25%) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.

Yield: 8.1 g

Boiling point: 110°-130° C./0.04 mbar

b) 4-Aminomethyl-4-hydroxypiperidine dihydrochloride

1 g (4.9 mmol) of ethyl 4-aminomethyl-4-hydroxypiperidine-1-carboxylate is heated overnight under reflux with 10 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are triturated with acetone, filtered off with suction and dried in a vacuum desiccator over P4 O10.

5.2 g (28 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate are added dropwise to 30 ml of methylamine solution (25% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and recrystallized from petroleum ether (hygroscopic crystals).

Yield: 3.3 g

b) 4-Hydroxy-4-methylaminomethylpiperidine dihydrochloride

3 g (13.9 mmol) of ethyl 4-hydroxy-4-methylaminomethylpiperidine-1-carboxylate are heated overnight under reflux with 30 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are stirred with acetone, filtered off with suction and dried in a vacuum desiccator over P4 O10.

5.2 g (28 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate are added dropwise to 30 ml of dimethylamine solution (40% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.

Yield: 5.2 g

Boiling point: 150°-155° C./3 mbar

b) 4-Dimethylaminomethyl-4-hydroxypiperidine dihydrochloride

4.5 g (19.4 mmol) of ethyl 4-dimethylaminomethyl-4-hydroxypiperidine-1-carboxylate are heated overnight under reflux with 35 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are triturated with acetone, filtered off with suction and dried in a vacuum desiccator over P4 O10.

5.7 g (30.8 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate are added dropwise to 30 ml of ethylamine solution (50% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.

Yield: 5.5 g

Boiling point: 100°-104° C./0.01 mbar

b) 4-Ethylaminomethyl-4-hydroxypiperidine dihydrochloride

4.6 g (20 mmol) of ethyl 4-ethylaminomethyl-4-hydroxypiperidine-1-carboxylate are heated overnight under reflux with 35 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are triturated with acetone, filtered off with suction and dried in a vacuum desiccator over P4 O10.

Yield: 4.2 g

Melting point: 225°-229° C.

EXAMPLE M3-Hydroxy-3-methylpyrrolidine

15 g (78.4 mmol) of 1-benzyl-3-hydroxy-3-methylpyrrolidine (European Patent Application 132,845) are dissolved in 150 ml of ethanol and hydrogenated on 2 g of palladium/active carbon (10% Pd) at 90° C. and 100 bar. The catalyst is subsequently filtered off with suction, the filtrate is concentrated and the residue is distilled.

9.6 g (50 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane are added dropwise to 50 ml of dimethylamine solution (50%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.

Yield: 10.3 g

Boiling point: 94° C./0.05 mbar

b) 3-Dimethylaminomethyl-3-hydroxypyrrolidine

9.4 g (39 mmol) of 1-benzyl-3-dimethylaminomethyl-3-hydroxypyrrolidine in 60 ml of methanol are hydrogenated using 2 g of palladium/active carbon (5%) at 100° C. and 90 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.

10 g (45 mmol) of 1-benzyl-3-hydroxy-3-methoxymethylpyrrolidine are hydrogenated using 3 g of Pd/active carbon (10% Pd) in 200 ml of methanol at 100° C. and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.

3.2 g (80 mmol) of NaOH are dissolved in 40 ml of water, 15.6 g (75 mmol) of 3-aminomethyl-1-benzyl-3-hydroxypyrrolidine and 50 ml of tert.-butanol are added and 17.7 g (79 mmol) of di-tert.-butyl dicarbonate are added dropwise at room temperature. After stirring overnight at room temperature, the product is filtered off with suction, the crystals are washed with CH2 Cl2 and the filtrate is extracted using CH2 Cl2. The extracts are dried over K2 CO3 and concentrated, and the residue is recrystallized from diisopropyl ether.

Yield: 19.1 g (83% of theory)

Melting point: 117°-119° C.

b) 3-tert.-Butoxycarbonylaminomethyl-3-hydroxypyrrolidine

18.7 g (61 mmol) of 1-benzyl-3-tert.-butoxycarbonylaminomethyl-3-hydroxypyrrolidine are dissolved in 120 ml of methanol and hydrogenated on 3 g of 5% strength Pd/active carbon at 90° C. and 100 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethyl acetate.

18.2 g (95 mmol) of 5-benzyl-1-oxa-5-azaspiro[2,4]heptane are added dropwise to 15.6 ml (0.115 mol) of benzylmethylamine in 300 ml of water and the mixture is stirred for 15 hours at room temperature. The product is extracted using CH2 Cl2, the extracts are dried using K2 CO3 and concentrated, and incipient distillation is carried out up to 160° C. (oil bath temperature).

Crude yield: 27.1 g

GC purity: 100%

b) 1-Benzyl-3-benzylmethylaminomethyl-3-methoxypyrrolidine

26 g (83 mmol) of crude 1-benzyl-3-benzylmethylaminomethyl-3-hydroxypyrrolidine in 50 ml of absolute tetrahydrofuran are added dropwise to 4 g of 80% strength sodium hydride in 100 ml of absolute tetrahydrofuran and the mixture is heated under reflux during this. After completion of hydrogen evolution, 12.4 g (87 mmol) of methyl iodide are slowly added dropwise and the mixture is subsequently heated overnight under reflux. The product is poured into ice water and extracted using toluene, the extract is dried over K2 CO3 and concentrated, and the residue is distilled.

Yield: 16.5 g

Boiling range: 140°-173° C./0.1-0.23 mbar

After repeated distillation:

Yield: 9.1 g (26% of theory)

GC purity: 80%

Boiling point: 141° C./0.07 mbar

c) 3-Methoxy-3-methylaminomethylpyrrolidine

8.4 g (20 mmol) of 80% strength 1-benzyl-3-benzylmethylaminomethyl-3-methoxypyrrolidine are dissolved in 100 ml of methanol, 4.4 ml of concentrated hydrochloric acid are added and the mixture is hydrogenated on 4 g of 10% strength Pd/active carbon at 80° C. and 120 bar. The catalyst is filtered off, the solution is concentrated, a solution of 3 g of KOH in 50 ml of methanol are added, KCL is filtered off and the solution is concentrated. The residue is taken up in CHCl3 again, the mixture is filtered, the solution is concentrated and the residue is distilled.

Yield: 1.7 g (59% of theory)

Boiling point: 33° C./0.08 mbar

Additional examples concerning intermediates following the examples A to Q.

To a mixture of 20.65 g (0,35 mol) isopropylamine and 75 ml water 18.9 g (0,1 mol) 5-benzyl-1-oxa-5-azaspiro[2.4]heptane are added dropwise and the mixture is stirred for 15 hours at room temperature. The mixture is extracted with chloroform, and the organic layer is separated, dried with potassiumcarbonate and finally the solvent is removed in vacuo.

Yield: 22.3 g (90% of theory)

Boiling point: 111° C./0,1 mbar.

b) 3-Isopropylaminomethyl-3-hydroxy-pyrrolidine

17.4 g (70 mmol) 1-Benzyl-isopropylaminomethyl-3-hydroxy-pyrrolidine are dissolved in 200 ml of ethanol. This solution is hydrogenated, using 10 g Pd-C (10%) at 100 bar/100° C. The catalyst is removed by filtration, the solvents are removed from the filtrate in vacuo.

Yield: 7.3 g (66% of theory)

Analogously to example R the compounds of the following examples are obtained from the respective amines:

c) An alternative synthesis fur 1-benzyl-3-(N-ethyl-N-methyl-aminomethyl)-3-hydroxy-pyrrolidine is as follows:

21.8 g (93 mmol) 1-benzyl-3-ethylaminomethyl-3-hydroxy-pyrrolidine (according to example Ca) are dissolved in a mixture of 9.5 g formic acid and 8.5 g 37% proof aqueous formaldehyde solution. The mixture is stirred at 80° C. for 4 hours. The solvents are removed in vacuo, the residue is taken up in water, and the pH is adjusted alkaline with potassium carbonate. The reaction mixture is then extracted with chloroforme, and the organic phase is dried with potassium carbonate. After filtration the organic solvent is removed in vacuo and the residue is destilled.

Yield: 17.8 g (85% of theory)

Boiling point: 110° C./0.08 mbar.

EXAMPLE Wa) 1-Benzyl-3-cyano-3-methoxy-pyrrolidine

To a mixture of 1.2 g trifluoroacetic acid and 1.2 g triethylamine in 200 ml dry dichloromethane 8.3 g (90 mmol, 90% proof) 2-methoxyacrylonitrile (J. Chem. Soc. 520, 1942) are added. Thereafter 28.5 g N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)-amine (Chem. Letters 1117, 1984) are added, and the mixture is stirred overnight at room temperature. The mixture is treated with a saturated solution of sodium hydrogencarbonate, dried with magnesiumsulfate, and finally the organic solvents are removed in vacuo and the residue is destilled.

Yield: 14 g (67% of theory)

Boiling point: 110° C./0.2 mbar

Purity: 93% proof (gas chromatography).

b) 3-Aminomethyl-1-bezyl-3-methoxy-pyrrolidine

The solution of 26.5 g (0.11 mol, 93% proof) 1-benzyl-3-cyano-3-methoxypyrrolidine in 300 ml methanole is hydrogenated at 15 g Raney-Ni at 60° C./100 bar H2. The catalyst is removed by filtration, the methanol is removed in vacuo, and the residue is destilled.

To a mixture of 19.5 g (88.5 mmol) 3-amino-methyl-1-benzyl-3-methoxy-pyrrolidine and 100 ml tert.-butanole 3.7 g sodium hydroxyde in 90 ml water are added. Thereafter 20 g pyro-carbonic acid-tert.-butylester is added dropwise. The mixture is stirred overnight at room temperature, and the precipitates are removed by filtration. The filtrate is extracted with chloroform, and the organic layer is separated and dried with magnesiumsulfate. The organic solvents are removed in vacuo, and the residue is destilled.

Yield: 26 g (91.7% of theory)

Boiling point: 155°-160° C./0.02 mbar.

d) 3-(tert.-Butoxycarboxylamino-methyl)-3-methoxy-pyrrolidine

12 g (37.4 mmol) 1-benzyl-3-(tert.-butoxy-carbonylamino-methyl)-3-methoxypyrrolidine is desolved in 150 ml ethanol. This solution is hydrogeneted at 4 g Pd-carbon (10%) at 100° C./100 bar H2. The catalyst is removed by filtration, and the organic solvents are removed in vacuo. The residue is destilled.

6.5 g Lithium aluminum hydride are suspended in 250 ml of dry diethylether. 42 g (0.16 mol) 1-benzyl-3-methoxypyrrolidine-3-carboxylic acidmethylester are added dropwise. The mixture is stirred for 2 hours under reflux. Thereafter 6.5 ml of water, 6.5 ml 15% proof KOH and 6.5 ml of water are added, the inorganic salts are removed by filtration and washed twice with tetrahydrofurane. The organic solvents are removed from the filtrate in vacuo and the resedue is destilled.

Yield: 28.8 g (82% of theory)

Boiling point: 116°-120° C./0.03 mbar.

c) 3-Hydroxymethyl-3-methoxypyrrolidine

A 24.8 mmolar run according to example W d) yielded 1.2 g (36.9% of theory), boiling point 76° C./0.07 mbar.

EXAMPLE 1 ##STR52##

A mixture of 1.4 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 0.8 g (5.5 mmol) of 3-ethylaminomethyl-3-hydroxypyrrolidine in 10 ml of acetonitrile and 5 ml of dimethylformamide is heated under reflux for 1 hour. The suspension is concentrated in vacuo, the residue is stirred well with water, and the remaining precipitate is filtered off with suction, washed with water, dried and recrystallized from glycol monomethyl ether.

1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 0.8 g (5.5 mmol) of 3-ethylaminomethyl-3-hydroxypyrrolidine are added to 1.5 g (5 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 5 ml of dimethylformamide and the mixture is heated under reflux for 1 hour. The suspension is concentrated, and the residue is filtered off with suction, washed with water and brought into solution with a little 1:1 hydrochloric acid. The hydrochloride is precipitated by the addition of ethanol. It is filtered off with suction, washed with ethanol and dried at 100° in vacuo.

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 to give 1-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 202°-207°.

EXAMPLE 4 ##STR55##

1.5 g (5 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux for 1 hour with 2.2 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane and 1.12 g (5.5 mmol) of 3-hydroxy-3-methylaminomethylpyrrolidine dihydrochloride in 10 ml of acetonitrile and 5 ml of dimethylformamide. The suspension is concentrated, the residue is stirred with water and the undissolved product is filtered off with suction, washed with water and dried. The crude product obtained (1.97 g) is recrystallized from dimethylformamide.

1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 4, the crude product obtained (1.75 g) is dissolved in 10 ml of 1:1 hydrochloric acid, and the hydrochloride is precipitated by adding ethanol, filtered off with suction, washed with ethanol and dried at 100° in vacuo.

3.3 g (30 mmol) of 1,4-diazabicyclo[2.2.2]octane and 2.5 g (11 mmol) of 4-ethylaminomethyl-4-hydroxypiperidine dihydrochloride are added to 2.65 g (10 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a mixture of 20 ml of acetonitrile and 10 ml of dimethylformamide and the mixture is heated under reflux for 1 hour. The suspension is concentrated, the residue is stirred with water (pH 7), and the precipitate is filtered off with suction, washed with water, dried and recrystallized from dimethylformamide.

1.3 g (5 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux for 1 hour with 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2.2]octane and 540 mg (5.4 mmol) of 3-hydroxy-3-methylpyrrolidine in 10 ml of acetonitrile and 5 ml of dimethylformamide. The suspension is concentrated, the residue is stirred with water, and the precipitate is filtered off with suction, washed with water, recrystallized from dimethylformamide and dried at 100° in vacuo. Yield: 1.4 g (81% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-hydroxy-3-methyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 315°-320° (with decomposition).

EXAMPLE 12 ##STR63##

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 11 with 1,4-dioxa-7-azaspiro[4.4]nonane to give 1-cyclopropyl-7-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 229°-230°.

EXAMPLE 13 ##STR64##

2 g of 1-cyclopropyl-7-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 100 ml of methanol and stirred for 2 hours at room temperature with 100 ml of 1:1 hydrochloric acid. The suspension is concentrated and the residue is recrystallized from dimethylformamide. Yield: 1 g (52% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-pyrrolidinyl)-3-quinolinecarboxylic acid of melting point 286°-288° (with decomposition).

EXAMPLE 14 ##STR65##

3-Aminomethyl-3-hydroxypyrrolidine is reacted according to Example 1 to give 7-(3-aminomethyl-3-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 248° C. (with decomposition).

8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 14, the product obtained is purified by chromatography on silica gel using dichloromethane/methanol/20% aqueous ammonia solution (2:4:1) as eluant and 7-(3-aminomethyl-3-hydroxy-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 240°-243° C. (with decomposition) are obtained.

FAB mass spectrum: m/e 396 [(M+H)+ ], 368 [(M+H-CO)+ ]

EXAMPLE 16 ##STR67##

1.42 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated under reflux for 1 hour in a mixture of 10 ml of acetonitrile and 5 ml of dimethylformamide and 0.8 g (5.6 mmol) of 3-hydroxy-3-dimethylaminomethyl-pyrrolidine and 1.1 g (10 mmol) of 1,4-diazabicyclo[2.2,2]octane. The suspension is concentrated, water is added to the residue and the mixture is acidified with dilute hydrochloric acid (1:1). The salt which crystallizes out is filtered off with suction and recrystallized from dimethylformamide. Yield: 1.1 g (50% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-3-dimethylaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 292°-295° C. (with decomposition).

a) A mixture of 6 g (20 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.5 g (22.7 mmol) of 1,4-diazabicyclo[2.2.2]octane and 4.2 g (20 mmol) of 3-tert.-butoxycarbonylaminomethyl-3-hydroxypyrrolidine in 40 ml of acetonitrile and 20 ml of dimethylformamide is heated under reflux for 3 hours. The solution is concentrated in vacuo, the residue is stirred with water, and the undissolved precipitate is filtered off with suction, washed with water and dried.

b) 9.5 g (19 mmol) of the product from Example 18a) are stirred for 30 minutes at room temperature in 300 ml of 1:1 hydrochloric acid. The mixture is filtered and the filtrate is concentrated at 35° C./12 mbar. The residue is recrystallized from glycol monomethyl ether.

3-Hydroxy-3-methoxymethylpyrrolidine is reacted analogously to Example 1 and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-3-methoxymethyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 230°-232° (with decomposition) (recrystallized from dimethylformamide) is obtained.

EXAMPLE 20 ##STR71##

3-Methoxy-3-methylaminomethylpyrrolidine is reacted analogously to Example 1 and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methoxy-3-methylaminomethyl-1-pyrrolidinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 245°-247° C. (with decomposition) (recrystallized from dimethylformamide) are obtained.

Following the description of example 1 the compound is reacted with 3-dimethylaminomethyl-3-hydroxy-1-pyrrolidine and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-demithylaminomethyl-3-hydroxy-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid, melting point 203°-206° C. (decomposition) is obtained.

A mixture of 2.2 g (5 mmol) 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-dimethylaminomethyl-3-hydroxy-1-pyrrolidinyl)-4-oxo-3-quinoline carboxylic acid and 250 mg 4-dimethylaminopyridine in 80 ml of dry pyridine are treated with 2.5 ml of acetic acid anhydride. The mixture is stirred for 15 hours at room temperature. The organic solvents are removed from the suspension obtained, ice cold water is added to the residue and the precipitates are isolated by filtration washed with water and ethanol and dried.

a) Analogously to example 16, using 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 1-cyclopropyl-7-(3-dimethylaminomethyl-3-hydroxy-1-pyrrolindyl)-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, melting point 225°-229° C. (decomposition) is obtained. The melting point of the respective hydrochlorid is 280°-286° C. (decomposition).

b) 2.5 g (5.9 mmol) of the product according to example 39 a are dissolved 25 ml pyridine and 25 ml saturated ethanolic amoniasolution is added. The mixture is heated during 12 hours in an autoclave to 125° C., and the organic solvents are thereafter removed in vacuo. From the residue the title compound is isolated by chromatography (SiO2 ; dichloromethane-methanol-20% NH3 -solution=110:80:15).

1.97 g (7 mmol) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are dissolved in 21 ml acetonitrile and 2.0 g (14 mmol) 3-dimethylaminomethyl-3-hydroxypyrrolidine are added. The mixture is stirred under a dry atmosphere for 12 hours at room temperature. The precipitate obtained is isolated and the title compound is obtained by chromatography (SiO2 ; dichloromethane-methanol-17% NH3 in water=30:8:1).

Yield: 2.2 g (81% of theory) 1-cyclopropyl-7-(3-dimethyl-aminomethyl-3-hydroxy-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 1.9 g of this compound are dissolved in 20 ml semiconcentrated hydrochloride acid, the volatile components of the solution are removed in vacuo, and the residue is taken up in ethanol. The unsoluble components are removed by filtration, and dried at 100° C. in vacuo.

0.8 g of the product of example 20 is heated in a mixture of 25 ml 87% proof formic acid and 25 ml 37% proof aqueous formaldehyde solution under reflux for 4 hours. From the yellow solution the volatile components are removed in vacuo, and from the residue the title compound is isolated by chromatography (SiO2 ; dichloromethane-methanol=95:5→dichlormethane-methanol 20% NH3 aqueous solution=2:4:1).

a) 1.91 g (5 mmol) 7-chlor-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid-ethylester is dissolved in 20 ml acetonitril. 864 mg (6 mmol) 3-dimethylaminomethyl-3-hydroxy-pyrrolidine and 672 mg (6 mmol) 1,4-diazabicyclo[2.2.2]octane are added, and the mixture is stirred for 4 hours at room temperature. Thereafter 20 ml of water are added, and the pH is adjusted to 9 with deluted NaOH. The precipitate is isolated by filtration, washed with water and dried in vacuo.

b) 1.51 g of the product of example 45 a is suspended in a mixture of acetic acid and 6n-hydrochloric acid (1:1), and the mixture is heated to reflux for 5 hours. The volatile constituents are removed in vacuo, the residue is taken up in water, the precipitates isolated by filtration and dried in vacuo.

It will be appreciated that the instant specification and claims are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.